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J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2017 September 01. Published in final edited form as: J Acquir Immune Defic Syndr. 2016 September 1; 73(1): 63–68. doi:10.1097/QAI.0000000000001010.

APOL1 Renal Risk Variants are Associated with Chronic Kidney Disease in Children and Youth with Perinatal HIV infection Murli U. Purswani, MD1, Kunjal Patel, DSc, MPH2, Cheryl A. Winkler, PhD3, Stephen A. Spector, MD4, Rohan Hazra, MD5, George R. Seage III, Dsc, MPH2, Lynne Mofenson, MD5, Brad Karalius, MPH2, Gwendolyn B. Scott, MD6, Russell B. Van Dyke, MD7, Jeffrey B. Kopp, MD8, and the Pediatric HIV/AIDS Cohort Study

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1

Division of Pediatric Infectious Disease, Department of Pediatrics, Bronx-Lebanon Hospital Center, Albert Einstein College of Medicine, Bronx, NY, United States.

2

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, United States.

3

Basic Science Laboratory, Center for Cancer Research, National Cancer Institute (NCI), Leidos Biomedical Inc. Frederick National Laboratory, Frederick, MD, United States. 4

Department of Pediatrics, University of California San Diego (UCSD), La Jolla, CA, and Rady Children's Hospital, San Diego, CA, United States. 5

Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States.

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6

Miller School of Medicine, University of Miami, Miami, FL, United States.

7

Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA.

8

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.

Corresponding author (same address for reprint requests): Murli U. Purswani, 1685 Morris Avenue, Suite 1G, Bronx, NY 10457, Tel: 718 960 1010; Fax: 718 960 1011; [email protected]. Presentations at meetings: Data in this manuscript has been previously presented in part as a poster at the annual Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, February 20-23, 2015; a poster at the annual meeting of the Pediatric Academic Societies (PAS) in Washington DC, May 5, 2013; and as a platform presentation at the annual meeting of the Eastern Society for Pediatric Research (ESPR) in Philadelphia, PA, in March 23, 2013.

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Conflicts of Interest No conflicts of interest were declared by all the authors. The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of the National Institutes of Health or U.S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. AUTHOR CONTRIBUTIONS: All authors meet authorship criteria. Brad Karalius and Kunjal Patel had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Conception and design of the study: Kopp, Purswani and Patel Acquisition of data, analysis and interpretation of data: All authors Drafting of manuscript: Purswani, Kopp, Patel, and Winkler Critical revision of Manuscript: All authors Final approval of submitted version: All authors Statistical analysis: Karalius and Patel Administrative, technical or material support: All authors Supervision of the study: Purswani, Kopp, and Patel

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Abstract Author Manuscript

APOL1 renal risk alleles are associated with chronic kidney disease (CKD) in adults, with the strongest effect being for HIV-associated nephropathy. Their role in youth with perinatal HIV infection (PHIV) has not been studied. In a nested case-control study of 451 PHIV participants in the Pediatric HIV/AIDS Cohort Study, we found a 3.5-fold increase odds of CKD in those carrying high-risk APOL1 genotypes using a recessive model (95% confidence interval [CI]: 1.2-10.0). We report an unadjusted incidence of 1.2 CKD cases/100 person-years (95% CI: 0.5, 2.5) in PHIV youth carrying APOL1 high-risk genotypes, with important implications for subSaharan Africa.

Keywords

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Perinatal; HIV; Chronic kidney disease; APOL1; African ancestry; Youth

Introduction Genetic variants of APOL1, encoding apolipoprotein L1, are strongly associated with chronic kidney disease (CKD) in individuals with sub-Saharan African ancestry1. Risk allele frequency is highest in West Africa, with lower prevalence elsewhere in sub-Saharan Africa2 Risk alleles are absent from populations outside Africa, unless population admixture has occurred. African Americans have a ~35% prevalence of APOL1 risk alleles, while 12-14% of individuals have high-risk genotypes comprising two risk alleles, inherited in a homozygous or compound heterozygous state3,4.

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Carriage of high-risk APOL1 genotypes increases CKD risk in adults4-10. The strongest association is for HIV-associated nephropathy (HIVAN) with odds ratios (OR) of 29 in the USA4 and 89 in South Africa10. A spectrum of CKD, described in children born with HIV infection, includes HIVAN, nephrotic syndrome, and various forms of immune-complex glomerulonephritis11-16. The association between APOL1 variants and CKD in these children has not been investigated. We evaluated this relationship in a large U.S. cohort of youth with perinatal HIV-1 infection (PHIV). As ancestry may confound association between APOL1 risk variants and CKD, we determined continental ancestry with a genetic panel, and adjusted for African ancestry in our analysis. We also evaluated the association between self-reported race and CKD, and African ancestry and CKD.

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Methods The Adolescent Master Protocol (AMP) of the Pediatric HIV/AIDS Cohort Study is an ongoing prospective cohort study of youth with PHIV designed to evaluate the impact of HIV and antiretroviral therapy on long term outcomes17. Between 2007 and 2009, 451 PHIV participants aged 7 to 16 years with comprehensive medical history since birth were enrolled at 15 sites within the USA and Puerto Rico. Participating sites and the Harvard T.H. Chan School of Public Health obtained Institutional Review Board approvals, and consent/assent

J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2017 September 01.

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was obtained from parents/legal guardians and participants. This study analyzed data as of January 1, 2014. DNA was extracted from saliva and buccal cells from participants who consented for genetic testing. Continental ancestry across five super-populations (Africa, Eurasia, East Asia, Americas, and Oceania) was determined using a panel of ancestry informative markers18-20. APOL1 genotyping was performed for two renal risk alleles: G1 (coding variants rs73885319A>G [p.S342G] and rs60910145G>T [p.I384M]) and G2 (6 base-pair deletion, rs71785313), by Taqman assays (Applied Biosystems, Foster City, CA)4. Carriage of two APOL1 risk alleles (G1/G1, G1/G2, or G2/G2) was defined as high-risk for renal disease; possession of zero or one risk allele (+/+, G1/+ or G2/+) was considered low-risk for renal disease.

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We performed a nested case control study. Cases of CKD were defined as a clinical diagnosis established by chart documentation of nephropathy, nephrotic syndrome, chronic renal failure, and/or focal segmental glomerulosclerosis (FSGS), or by clinical tests, either of the following: 1) persistent proteinuria for >6 months established by ≥ 2 sequential urine protein/creatinine ratios (UPC) ≥0.2g/g not followed by a UPC 80% vs. ≤ 25%

2.8 (0.5, 14.9)

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The unadjusted ORs were for APOL1 risk allele status, race and ancestry, individually; the ORs for APOL1 risk allele status were adjusted for African ancestry.

1

Of 27 CKD cases, 26 with APOL1 genotype data, all with self-reported race (1/24 black participants with missing genotype)

2

Of 207 controls, 194 with APOL1 genotype data, 193 with self-reported race (6/140 black participants with missing genotype)

Author Manuscript Author Manuscript J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2017 September 01.

Brief Report: APOL1 Renal Risk Variants Are Associated With Chronic Kidney Disease in Children and Youth With Perinatal HIV Infection.

APOL1 renal risk alleles are associated with chronic kidney disease (CKD) in adults, with the strongest effect being for HIV-associated nephropathy. T...
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